Joshi Nidhi, Dunleavy Katie M, Beel Kaitlin M, Engel Tiffany A, Thompson Andrew R, John Felix L, Thomas David D, Levinson Nicholas M
Department of Pharmacology and Masonic Cancer Center, University of Minnesota, 312 Church St. SE, Minneapolis, MN, 55455, USA.
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 312 Church St. SE, Minneapolis, MN, 55455, USA.
Biochem J. 2025 Mar 28;482(8):369-81. doi: 10.1042/BCJ20240726.
The oncoprotein c-Myc is overexpressed or mutated in a large fraction of human cancers. The stability of c-Myc is controlled by phosphorylation of T58 and S62 within a conserved degron motif in the N-terminal transactivation domain, which triggers recruitment of the SCF ubiquitin ligase. The kinase Aurora A (AurA) has been shown to bind to both c-Myc and its paralog N-Myc and to promote their stability by interfering with ubiquitination and degradation. Here we show, using NMR and FRET experiments, that AurA binds to c-Myc through several discrete interactions spanning 145 residues within its transactivation domain. AurA binding to c-Myc is enhanced by phosphorylation of the T58/S62 degron, demonstrating that the kinase recognizes the pool of c-Myc that has been marked for degradation by the ubiquitin proteasome pathway. Although AurA binds to segments of c-Myc flanking the degron, it does not appear to form extensive interactions with the phosphorylated degron itself, potentially leaving it accessible on the AurA surface. These observations establish a foundation for understanding the role of AurA in regulating c-Myc ubiquitination and degradation.
癌蛋白c-Myc在大部分人类癌症中过度表达或发生突变。c-Myc的稳定性由位于N端反式激活结构域中一个保守降解基序内的T58和S62位点的磷酸化所控制，该磷酸化会触发SCF泛素连接酶的募集。激酶Aurora A（AurA）已被证明可与c-Myc及其旁系同源物N-Myc结合，并通过干扰泛素化和降解来促进它们的稳定性。在此，我们利用核磁共振（NMR）和荧光共振能量转移（FRET）实验表明，AurA通过其反式激活结构域内跨越145个残基的几个离散相互作用与c-Myc结合。T58/S62降解基序的磷酸化增强了AurA与c-Myc的结合，这表明该激酶识别已被泛素蛋白酶体途径标记用于降解的c-Myc池。尽管AurA与降解基序两侧的c-Myc片段结合，但它似乎并未与磷酸化的降解基序本身形成广泛的相互作用，这可能使其在AurA表面仍可被接触到。这些观察结果为理解AurA在调节c-Myc泛素化和降解中的作用奠定了基础。
